Update on Advanced Breast Cancer Treatment - Episode 12

Neoadjuvant Treatment in Triple-Negative Breast Cancer

Transcript:Adam M. Brufsky, MD: So, the last part of our discussion really is, I think, addressing one of the big challenges that we have with breast cancer. I think we’ve done a really good job. We could do better, but we’ve done a really good job so far with ER-positive breast cancer. I think we’ve done a very good job with HER2-positive breast cancer. But really, triple-negative breast cancer now is a topic that is, I think, on everybody’s minds. First of all, what is it? I think we’re not 100% sure what triple-negative breast cancer really is. Is it a diagnosis of exclusion? Does it have real characteristics? But, more importantly, what do we do when someone comes in to our clinics with that diagnosis of triple-negative breast cancer?

I think what’s really on everybody’s minds after San Antonio this year is really, what’s the proper management, at least for neoadjuvant therapy, for triple-negative breast cancer? I think a lot of women who come in to us now will get neoadjuvant therapy if you have surgeons that are into that sort of thing, if you’re in part of the country or internationally where the surgeons agree that if someone is getting chemotherapy afterwards, they might as well as just get it beforehand. And so I [ask], what is the proper management now? Should we be adding platinum agents? I’ll start with Christy. What do you think? Should we be adding platinum now in 2016?

Christy A. Russell, MD: In the neoadjuvant setting?

Adam M. Brufsky, MD: In the neoadjuvant setting with triple-negative breast cancer.

Christy A. Russell, MD: Well, I had been saying ‘No’ up until the von Minckwitz presentation at San Antonio. And I’m not sure I’m quite there yet, but that was a presentation where patients were on a regimen I wouldn’t use, paclitaxel plus non-pegylated liposomal doxorubicin.

Adam M. Brufsky, MD: Right. Does anybody use that regimen?

Christy A. Russell, MD: As the base therapy.

Hope S. Rugo, MD: We don’t have that drug approved the US.

Adam M. Brufsky, MD: Right, correct.

Christy A. Russell, MD: And it was given with or without carboplatin, although some patients also got bevacizumab as part of this trial, as well.

Adam M. Brufsky, MD: It was a very strange regimen.

Christy A. Russell, MD: And my impression had been that the triple-negative patients who were actually benefitting from the carboplatin were always going to be the BRCA-mutated patients, and that’s what would fall out here—and that’s not what has fallen out.

Adam M. Brufsky, MD: Which is very unusual.

Christy A. Russell, MD: Right. So that the BRCA-mutated patients did not seem to get the benefit from adding carboplatin. Just the triple-negative patients who were wild-type BRCA did seem to get a significant advantage by adding carboplatin, not only in pathologic complete response rate, but also in what appears to translate to disease-free survival. And it has now made me think about it a little bit more. I’ve not yet added it.

Joyce A. O’Shaughnessy, MD: The thing I just want to point out about that is that they took out their alkylator. They took out the cyclophosphamide. Doxorubicin, of course, is a good DNA-damaging agent. We probably need that in a subset, at least, of these triple-negatives that have homologous recombination deficiency. I worry whether that low dose of liposomal doxorubicin, at the 20/meter dose, was enough of a DNA damage. Now, platinum really nicely made up for this lack, and I think that raises a great question: is platinum a better DNA-damaging agent for those patients than cyclophosphamide? And I think that’s a really good question.

Adam M. Brufsky, MD: Or what that says, is that if they had an inferior neoadjuvant regimen that the carboplatin made up for.

Joyce A. O’Shaughnessy, MD: Precisely, right. Right.

Adam M. Brufsky, MD: I never thought of it. That’s actually a good way of thinking about it.

Joyce A. O’Shaughnessy, MD: And it’s corroborated by the 40603 CALGB trial by William Sikov that also updated, and disease-free survival was not improved with the addition of the carboplatin to the paclitaxel preoperatively. There was an intriguing 5% difference in terms of the absolute numbers, but it wasn’t significant. But, of course, as Angie DeMichele with her lovely discussion said, neither trial was really powered to look at disease-free survival.

Hope S. Rugo, MD: They gave the carboplatin at AUC of 2 in the GBG trial and AUC of 6 for only four doses. I mean, there may be something to longer exposure. But I really have thought about it similarly to what you’re saying; the lower dose of anthracycline may have made a difference, and the carboplatin dose was low. It was an AUC of 1.5 because it was too toxic, otherwise, altogether.

Adam M. Brufsky, MD: It’s harder to deliver. But it’s making up for an inferior baseline regimen. That’s a good point. I never thought of that.

Joyce A. O’Shaughnessy, MD: Angie’s bottom line, which I thought was really great, was that it’s really not probably the standard of care at this time. We really need the larger trials powered for disease-free survival. However, for the individual patient, perhaps the BRCA-mutant patient or the very high-risk patient, you really want it because there was a delta 13% improvement in pathologic complete response rate—so for the patient that really wants breast-conserving surgery or when you need a very, very robust response. She left it open, and I agree with that. I think we may all use it from time to time in patients, but not as standard of care.

Adam M. Brufsky, MD: Well, let’s go to the Sikov regimen. Let’s talk about the Sikov trial. The Sikov trial, if I’m not mistaken, was typical AC—weekly paclitaxel with or without carboplatin.

Hope S. Rugo, MD: AUC of 6.

Adam M. Brufsky, MD: AUC of 6 every three weeks. So that’s typical. That’s like we can all use AC—weekly Taxol—and we all would use carboplatin to AUC of 6. A lot of us may use it weekly, who knows. But, nonetheless, that regimen didn’t seem to show a disease-free survival benefit.

Hope S. Rugo, MD: Right. But I think that, again, the trials were not powered to show a survival difference. And the delta makes all of the difference here in terms of what happens to these patients. And so the other thing, which I think is a really important point that Angie made and we talk about a lot about in the I-SPY 2 network, is that if you look at residual cancer burden versus looking at pathologic complete response (CR), you have different numbers. And in our data set, even from I-SPY 1 looking at standard therapy, the patients who had a residual cancer burden (RCB) that was minimal, but who had residual invasive cancer, had the same outcome as the people who had no invasive cancer. So you know you’re in a very complicated situation where you’re trying to look at what happens to people over time with disease-free survival benefit. And a lot of people with triple-negative breast cancer have RCB 0 or 1. So if you maybe looked at that, which, of course, they’ll do over the future, it will change the pathologic CR rate. And in I-SPY 2, when we’ve had these pathologists specially trained by Fraser Symmans from MD Anderson, our pathologic CR rates have gone down. Because, basically, when you have really specialized pathologists looking at these pathologic CR rates, you get a different rate than when you report it in a large study where each institution does their own.

So it’s a complicated area, and I don’t think we know. What I’ve done personally, and I think many of us may do is that when you see these poor responders, we tend to add. So for a poor responder with triple-negative disease, I’ll add a platinum agent as opposed to starting with it, since we already know we get a reasonable pathologic CR rate in those patients. And we’re now designing clinical trials for those patients, whether it’s postsurgery or pre-surgery, where you take the patients who are poor responders and part way through, which we have to figure out, we add in something new to see if we can really change the outcome of these patients.

Adam M. Brufsky, MD: But that’s the question. Is changing the pathologic CR rate by 10%, just like in Angie’s presentation, going to make a difference clinically in terms of disease-free survival?

Joyce A. O’Shaughnessy, MD: I do want to just mention very briefly the CREATE-X trial because that was one of the big data sets coming out of San Antonio, speaking about what Hope just said about those patients who don’t get the pathologic CRs, not the RBC 1s which do very, very well.

Hope S. Rugo, MD: Fascinating trial.

Adam M. Brufsky, MD: It was but…

Joyce A. O’Shaughnessy, MD: Fascinating trial, relatively small, 900 patients; a mixture of triple-negative and ER-positive patients who received eight cycles of capecitabine versus not if they had either nodes positive, residual, or disease in breast, and had improvement in both disease-free and overall survival with the capecitabine— eight cycles, six months. But the benefit looked like it was mostly in the triple-negative population—very, very interesting data. My personal opinion is that it is something worth discussing with some patients.

Adam M. Brufsky, MD: It is, but let me ask you a question: so the question, and maybe they answered this afterward somewhere, is, what was their original pathologic CR rate of their original chemotherapy in that CREATE-X trial?

Hope S. Rugo, MD: They didn’t enroll patients in that way, so they weren’t enrolled at the start of neoadjuvant therapy; they just came with residual disease. So you can’t really go back because you don’t have an N to start with.

Adam M. Brufsky, MD: That’s the problem. I have no idea whether they had inferior standard of care.

Joyce A. O’Shaughnessy, MD: No, no, we do know what they got. No, no, it’s quite clear that 95% of them got anthracyclines or taxanes, either sequentially or in combination.

Adam M. Brufsky, MD: But what were the doses? Were they delivered properly?

Hope S. Rugo, MD: No, he didn’t know that at the time of the presentation. But they’ll obviously figure it out for their next one.

Adam M. Brufsky, MD: Well, and for the publication. That’s one I’d like to see before I go any further with that.

Hope S. Rugo, MD: I think the thing is that all trials that are looking at postneoadjuvant therapy don’t control the neoadjuvant therapy, except for to say, ‘You need an anthracycline and taxane.’

Adam M. Brufsky, MD: The lesson, hopefully, is when you see a postneoadjuvant trial, they will specify very clearly the doses and the delivery of the neoadjuvant chemotherapy.

Joyce A. O’Shaughnessy, MD: I think it’s important, yes, yes.

Adam M. Brufsky, MD: It’s extremely important because the simple hypothesis is just that they got inferior neoadjuvant chemotherapy.

Hope S. Rugo, MD: You know what else is really interesting, I have never had a patient—actually, it’s not true—I might have had two patients ever tolerate 2500 mg/m2 of capecitabine, and that’s the dose they gave and their dose intensity was very good. And we know that the metabolism of capecitabine is different in many, not all, Asian people based on differences in pharmacogenomics. And I think the exposure to [the] drug may just be different. It’s a fascinating question about whether or not you would see a difference not just in toxicity, but in efficacy. Because, Joyce, you did the combination study. What was your dose of capecitabine?

Joyce A. O’Shaughnessy, MD: At the end of the day, we were really able to get in around 1650 mg/m2. We had to dose-reduce.

Hope S. Rugo, MD: Because of the combination?

Joyce A. O’Shaughnessy, MD: Yeah, because of the combination.

Sara A. Hurvitz, MD: But they had a 25% dose reduction in that study.

Adam M. Brufsky, MD: Yeah, I mean most people start at 2 g/m2.

Hope S. Rugo, MD: But then we dose-reduce from there, you see, so we give less.

Adam M. Brufsky, MD: We do.

Joyce A. O’Shaughnessy, MD: We do.

Christy A. Russell, MD: What I thought was more fascinating is when I use Xeloda as a single agent in triple-negative metastatic breast cancer. I see really low response rates, really short. And you give it to someone who’s ER-positive and you get this really prolonged benefit on this drug at the lowest doses.

Adam M. Brufsky, MD: And it was given in one of the GEPAR series of trials, remember? That’s when Gunter von Minckwitz got up, actually, and spoke and said we’ve given this. I forgot, it was like GeparQuattro or whatever one it was, and it didn’t really add to the pathologic CR rate. So, if you had TAC times, I think, 3 or 4…

Hope S. Rugo, MD: And then they switched to vinorelbine and capecitabine.

Adam M. Brufsky, MD: Either vinorelbine or capecitabine, you didn’t respond. You didn’t have additional response.

Joyce A. O’Shaughnessy, MD: But the systemic response in that GeparTrio was surprising that it actually came through with an improved disease-free survival.

Hope S. Rugo, MD: They did really well, yeah.

Joyce A. O’Shaughnessy, MD: Two other points, FinXX, it did.

Adam M. Brufsky, MD: Yeah, it did. Yeah, I guess you’re right.

Joyce A. O’Shaughnessy, MD: In the systemic benefit. And also [the] US Oncology trial 01062 published in Clinical Cancer Research last year that added the capecitabine to the docetaxel, only four cycles. And then the FinXX trial which did six cycles of the capecitabine. If you look at the subsets in both, the triple-negative patients benefitted.

Adam M. Brufsky, MD: So in the systemic benefit though, not the breast benefit.

Joyce A. O’Shaughnessy, MD: Systemic.

Adam M. Brufsky, MD: So maybe there’s something there with the systemic benefit if it’s not in the breast. It’s a good point.

Hope S. Rugo, MD: You know, the trials are different because they gave it in combination and they gave lower doses; all three trials did. So I think it does, I agree.

Adam M. Brufsky, MD: There may be something there. I could be convinced.

Hope S. Rugo, MD: Yeah, it’s fascinating.

Adam M. Brufsky, MD: I don’t know. So you would think about using it now. I mean, the question for people listening to this, will you use it now?

Joyce A. O’Shaughnessy, MD: I think it has to be addressed in the next generation of trials. I mean, is it a control arm, etc?

Hope S. Rugo, MD: But if somebody has significant residual disease. And, again, I wouldn’t do it for a person who has RCB 1. But if they have positive nodes with triple-negative disease after a good neoadjuvant therapy, these patients have a poor outcome. So in a patient with a BRCA mutation, I’d probably use a platinum agent based on the Polish data, which are quite impressive.

Adam M. Brufsky, MD: In the Sikov trial, in Bill’s trial, was there analysis by BRCA status? I forget.

Hope S. Rugo, MD: The pathologic CR rate, it was higher with the patients who had BRCA mutations.

Adam M. Brufsky, MD: The BRCA but not the DFS, not the disease-free survival?

Hope S. Rugo, MD: No, they didn’t look at that.

Adam M. Brufsky, MD: They didn’t look at that.

Hope S. Rugo, MD: The numbers in all the trials are too small.

Adam M. Brufsky, MD: Too small.

Hope S. Rugo, MD: You really have to be careful about making that.

Adam M. Brufsky, MD: Would you use it in your patients, Sara?

Sara A. Hurvitz, MD: Capecitabine? Yeah.

Adam M. Brufsky, MD: Yeah. In the adjuvant setting?

Sara A. Hurvitz, MD: Yeah. Exactly what Hope has been saying and Joyce, as well. I think it warrants a discussion with patients who have had standard therapy and have a lot of residual disease if they’re hormone receptor—negative.

Adam M. Brufsky, MD: So it sounds like what I’m hearing is that basically all of us would agree that platinum agents in certain settings, maybe BRCA-positive, maybe high disease burden, and potentially adjuvant capecitabine in certain settings also. That’s what I’m hearing. Okay.

Transcript Edited for Clarity